Transcriptomic analysis reveals prognostic molecular signatures of stage I melanoma

Purpose: Previously identified transcriptomic signatures have been based on primary and metastatic melanomas with relatively few AJCC stage I tumors given difficulties in sampling small tumors. The advent of adjuvant therapies has highlighted the need for better prognostic and predictive biomarkers especially for AJCC stage I and II disease. Experimental Design: 687 primary melanoma transcriptomes were generated from the Leeds Melanoma Cohort (LMC). The prognostic value of existing signatures across all the AJCC stages was tested. Unsupervised clustering was performed and the prognostic value of the resultant signature was compared with that of sentinel node biopsy (SNB) and tested as a biomarker in three published immunotherapy datasets. Results: Previous Lund and TCGA signatures predicted outcome in the LMC dataset (P=10-8 to 10-4) but showed a significant interaction with AJCC stage (P=0.04) and did not predict outcome in stage I tumors (P=0.3 to 0.7). Consensus-based classification of the LMC dataset identified six classes which predicted outcome, notably in stage I disease. LMC class was a similar indicator of prognosis when compared to SNB and it added prognostic value to the genes reported by Gerami et al. One particular LMC class consistently predicted poor outcome in patients receiving immunotherapy in two of three tested datasets. Biological characterisation of this class revealed high JUN and AXL expression and evidence of epithelial to mesenchymal transition. Conclusion: A transcriptomic signature of primary melanoma was identified with prognostic value, including in stage I melanoma and in patients undergoing immunotherapy.